Correction of Hyponatremia May Be a Treatment Stratification Biomarker: A Two-Stage Systematic Review and Meta-Analysis

Changes in serum sodium concentration ([Na(+)](serum)) can permit evaluation of the treatment effect of vasopressin antagonists (vaptans) in patients with worsening heart failure (HF) or cirrhotic ascites; that is, they may act as a treatment stratification biomarker. A two-stage systematic review and meta-analysis were carried out and contextualized by experts in fluid resuscitation and translational pharmacology (registration ID in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42017051440). Meta-analysis of aggregated dichotomous outcomes was performed. Pooled estimates for correction of hyponatremia (normalization or an increase in [Na(+)](serum) of at least 3–5 mEq/L) under treatment with vaptans (Stage 1) and for clinical outcomes in both worsening HF (rehospitalization and/or death) and cirrhotic ascites (ascites worsening) when correction of hyponatremia is achieved (Stage 2) were calculated. The body of evidence was assessed. Correction of hyponatremia was achieved under vaptans (odds ratio (OR)/95% confidence interval (95% CI)/I(2)/number of studies (n): 7.48/4.95–11.30/58%/15). Clinical outcomes in both worsening HF and cirrhotic ascites improved when correction of hyponatremia was achieved (OR/95% CI/I(2)/n: 0.51/0.26–0.99/52%/3). Despite the appropriateness of the study design, however, there are too few trials to consider that correction of hyponatremia is a treatment stratification biomarker. Patients with worsening HF or with cirrhotic ascites needing treatment with vaptans, have better clinical outcomes when correction of hyponatremia is achieved. However, the evidence base needs to be enlarged to propose formally correction of hyponatremia as a new treatment stratification biomarker. Markers for use with drugs are needed to improve outcomes related to the use of medicines.